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Volume 117 (2001)
- Issue 6 Pages 377-
- Issue 5 Pages 319-
- Issue 4 Pages 243-
- Issue 3 Pages 159-
- Issue 2 Pages 105-
- Issue 1 Pages 5-
Volume 117, Issue 5
Displaying 1-6 of 6 articles from this issue
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Reviews
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Nubuyuki TAKAHASHI, Teruo KAWADASubject area: Others
2001 Volume 117 Issue 5 Pages 319-327
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThe finding of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, thyroxine, vitamin D and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains. In mammals, the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes by separate genes: PPARα, PPARδ (also referred to as hNUC1 or PPARβ), and PPARγ. PPARs have been associated with several distinct biological programs. PPARs function as a heterodimer with the retinoid X receptor. This complex binds to sequences termed direct repeat-1 response element in enhancer sites of regulated genes and activates transcription upon ligand and coactivator binding. Three different PPAR subtypes have specific roles in different organs. PPARα, mainly expressed in liver, plays an important role in fatty acid metabolism. PPARγ predominantly is expressed in adipose cells. PPARδ displays a high level of expression in lipid-metabolizing organs such as small intestine, heart and adipose tissue. Naturally occurring and synthetic molecules (anti-hyperlipidemia and diabetic drugs) that are ligands for these nuclear receptors control transcriptional activity of PPARs. We believe that the pharmacological and genomic researches on PPAR will develop powerful tools for prevention and medical care against common diseases.View full abstractDownload PDF (1253K) -
Chiaki KAMEI, Chihiro OKUMASubject area: Others
2001 Volume 117 Issue 5 Pages 329-334
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThe role of central histamine in amygdaloid kindled seizures in rats was studied. Histamine content in the amygdala was significantly decreased after development of amygdaloid kindling. Intracerebroventricular (i.c.v.) injection of histamine resulted in inhibition of amygdaloid kindled seizures. The H1-agonists 2-methylhistamine and 2-thiazolylethylamine also inhibited amygdaloid kindled seizures. In addition, intraperitoneal (i.p.) injection of histidine and metoprine inhibited amygdaloid kindled seizures at doses that caused increases in histamine contents of the brain. H1-antagonists (diphenhydramine and chlorpheniramine) attenuated histamine- or histidine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and i.p. injections of H3-antagonists (thioperamide, AQ0145 and clobenpropit) resulted in a dose-related inhibition of amygdaloid kindled seizures. The effects of thioperamide and AQ0145 were inhibited by an H3-agonist (R)-α-methylhistamine and H1-antagonists. On the other hand, H2-antagonists showed no antagonistic effect. GABAmimetic drugs, diazepam, sodium valproate and muscimol potentiated the effect of clobenpropit. Bicuculline caused significant antagonism of the inhibition of amygdaloid kindled seizures induced by clobenpropit. These findings suggested that a histaminergic mechanism plays an important role in suppressing amygdaloid kindled seizures through histamine H1-receptors. In addition, an inhibition of amygdaloid kindled seizures induced by histamine is closely related with the action of GABA.View full abstractDownload PDF (681K)
Review on New Drug
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Hitoshi IKEDA, Yasuo SUGIYAMAArticle type: Others
Subject area: Others
2001 Volume 117 Issue 5 Pages 335-342
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSTakeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocininduced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucoselowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem to be due to the inhibitory action of pioglitazone on TNF-α production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator-activated receptor, (PPAR)-γ, that is related to differentiation of adipocytes, and the relationship between TNF-α production and PPAR-γ has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-γ may be involved in the mechanism of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.View full abstractDownload PDF (1067K) -
Toshiyuki MATSUNAGAArticle type: Others
Subject area: Others
2001 Volume 117 Issue 5 Pages 343-349
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAzithromycin (Zithromac®), a 15-membered ring macrolide antibacterial agent, was approved to be manufactured in Japan in March 2000. It showed good in vitro and/or in vivo antibacterial activities against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Peptostreptococcus micros, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae. Its activity against H. influenzae was particularly more potent than that of currently used macrolide antibacterial agents. After oral administration to patients, azithromycin was readily abserbed and became widely distributed throughout the body, achieving higher concentrations in tissues and phagocytic cells than in serum or plasma. Its distribution into phagocytes was as high as more than 10 times that of erythromycin, and azithromycin was readily released from phagocytes in the presence of S. aureus. In experimentally infected mice, the concentration of azithromycin was higher in infected tissues than in uninfected tissues, which indicated that azithromycin was selectively delivered to infected tissues by migrating phagocytes. These pharmacological and pharmacokinetic properties were reflected in good clinical results for the treatment of respiratory infections and other infections with once daily dosing for 3 days.View full abstractDownload PDF (627K) -
Jun HIROIArticle type: Others
Subject area: Others
2001 Volume 117 Issue 5 Pages 351-357
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSAtopic dermatitis (AD) is thought to be induced by a complex of various allergic reactions and T cells are implicated in its etiology. Since tacrolimus strongly inhibits T cell activation, tacrolimus ointment has been developed as a novel drug for AD throughout the world. Tacrolimus inhibits mast cell and eosinophil activation and antigen presenting activity of Langerhans cells in vitro. In the in vivo experimental animal models of AD, such as contact and spontaneous dermatitis in mice and repeated hapten treated skin inflammation in rats, tacrolimus ointment showed inhibitory activity. In clinical studies with AD patients in Japan, USA and Europe, tacrolimus ointment showed a marked effect. In comparative studies in Japan, it showed the same efficacy as a strong class steroid ointment on eczema at the trunk and extremities and superior efficacy at the face and neck compared to a medium class steroid. The most prominent adverse event is experienced at the local application site with reactions such as a burning sensation and erythema. Systemic side effects were rarely observed. While there is a possibility of skin infections when using tacrolimus, skin atrophy, even after long term treatment, was not observed. Thus tacrolimus ointment could be an efficient alternative to steroid ointment for AD.View full abstractDownload PDF (1322K)
Drug Development Now
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Hiroaki ARAKI, Koujiro FUTAGAMI, Yutaka GOMITAArticle type: Others
Subject area: Others
2001 Volume 117 Issue 5 Pages 359-366
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSIn a rapidly aging society, the number of patients becoming bed-ridden due to osteoporosis-related fracture has become a socially important health issue that includes the problem of adequate nursing. Recently, the introduction of a rapidly acting bone absorption suppressant with a clear mechanism accelerated the development of osteoporosis treatment. A selective estrogen receptor modulator in a estrogen preparation is expected, because it has antagonism for the acceptor of the reproductive organ. It is noted that a new steroid with a weak androgen action and estrogen- and progestogen-like actions both prevents bone quantity decrease in women and increases bone quantity in osteoporotic patients after menopause. The second and third generation of bisphosphanate is more powerful than etidronate, the first generation of bisphosphanate, allows continual medication, and is now in clinical trial. The introduction of new drugs, which have clear efficacy and fewer side effects may be expected, along with the combined use of the drugs in which action mechanisms differ. The introduction of pharmaceutical new approaches is also expected as the expression mechanism of osteoporosis is further clarified by basic studies.View full abstractDownload PDF (745K)
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